Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies from our laboratory and others indicate that contraction-induced mechanical loading of cultured neonatal rat ventricular myocytes produces many of the phenotypic changes associated with cardiomyocyte hypertrophy in vivo, and that these changes occur via the activation of serine-threonine protein kinases. These may include the extracellular regulated protein kinases (ERK1 and ERK2), the c-Jun N-terminal kinases (JNK1, JNK2, and JNK3), and one or more isoenzymes of protein kinase C. In this study, we assessed whether one or more of these kinases are activated by stimulated contraction, and whether activation was isoenzyme-specific. Low-density, quiescent cultures of neonatal rat ventricular myocytes were maintained in serum-free medium, or electrically stimulated to contract (3 Hz) for up to 48 h. ERK and JNK activation was assessed by Western blotting with polyclonal antibodies specific for the phosphorylated forms of both kinases. PKC activation was analysed by subcellular fractionation, detergent extraction, and Western blotting using isoenzyme-specific monoclonal antibodies. Stimulated contractile activity produced myocyte hypertrophy, as indicated by increased cell size, a 15+/-5% increase in total protein/DNA ratio, and induction of ANF and beta MHC gene transcription. Electrical pacing did not cause ERK1/2 or JNK1 activation, but increased JNK2 and JNK3 phosphorylation by;two-fold. Subcellular fractionation revealed a time-dependent increase in PKC delta, and to a much lesser extent PKC xi, in a Triton X-100-soluble membrane fraction within 5 min of the onset of stimulated contraction. PKC alpha was not activated by electrical pacing. These results indicate that contraction-induced mechanical loading acutely activates some but not all of the specific isoenzymes of JNKs and PKCs in cardiomyocytes.
 ...
PMID:Isoenzyme-specific protein kinase C and c-Jun N-terminal kinase activation by electrically stimulated contraction of neonatal rat ventricular myocytes. 1090 Jan 80

Microtubule-damaging agents arrest cells at G(2)/M and induce apoptosis in association with phosphorylation of the anti-apoptotic proteins Bcl-2 and Bcl-X(L). Because microtubule inhibitors activate JNK, we sought to determine whether JNK was responsible for Bcl-2/Bcl-X(L) phosphorylation in KB-3 cells treated with vinblastine. Two major endogenous forms of JNK, p46(JNK1) and p54(JNK2), were present in KB-3 cells, and both isoforms were activated by vinblastine as determined by Mono Q chromatography. We used antisense oligonucleotides (AS) to specifically inhibit their expression. A combination of AS-JNK1 with AS-JNK2 inhibited by 80% vinblastine-induced phosphorylation of two known JNK substrates, c-Jun and ATF-2. In addition, AS-JNK1/2 inhibited vinblastine-induced phosphorylation of Bcl-2 by 85% and that of Bcl-X(L) by 65%. Stable expression of the JNK scaffold protein JIP-1 blocked vinblastine-induced phosphorylation of c-Jun and ATF-2, but did not affect Bcl-2/Bcl-X(L) phosphorylation, confirming a bifurcation in JNK signaling involving both nuclear and non-nuclear substrates. Vinblastine-induced phosphorylation of Raf-1 was unaffected by AS-JNK1/2 and was associated with loss of activity for MEK substrate in vitro and inactivation of ERK in vivo. These results provide evidence for a direct role of the JNK pathway in apoptotic regulation through Bcl-2/Bcl-X(L) phosphorylation.
 ...
PMID:Vinblastine-induced phosphorylation of Bcl-2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade. 1091 35

The responses of mitogen-activated protein kinase (MAPK) family members, including ERK (extracellular signal-regulated kinase), JNK (c-Jun NH2-terminal kinase), and p38, in the metabolic responses to whole animal freezing (up to 24 h frozen at -2.5 degrees C) and thawing (up to 4 h at 5 degrees C after a 12 h freeze) were examined in four organs (liver, kidney, heart, brain) of the freeze-tolerant wood frog Rana sylvatica. Levels of the active phosphorylated form of p38 increased within 20 min as an early response to freezing in liver and kidney but rose later (after 12 h) in heart. Both JNK and p38 were activated during thawing in liver, kidney and heart with temporally-distinct patterns in each organ. The only MAPK response to freeze/thaw in frog brain was a transient elevation of p38 after 90 min thawing. ERK activity did not respond to freeze/thaw in any organ. The levels of c-Fos increased during freezing in kidney and brain whereas c-Jun was unaffected by freeze/thaw. Organ-specific responses by MAPKs, particularly p38, suggest that these may have roles in regulating metabolic or gene expression responses that may be adaptive in dealing with freezing stress or metabolic recovery during thawing.
 ...
PMID:Activation of mitogen-activated protein kinases during natural freezing and thawing in the wood frog. 1094 98

This article reviews recent results of studies aiming to elucidate modes of integrating signals initiated in ACTH receptors and FGF2 receptors, within the network system of signal transduction found in Y1 adrenocortical cells. These modes of signal integration should be central to the mechanisms underlying the regulation of the G0-->G1-->S transition in the adrenal cell cycle. FGF2 elicits a strong mitogenic response in G0/G1-arrested Y1 adrenocortical cells, that includes a) rapid and transient activation of extracellular signal-regulated kinases-mitogen-activated protein kinases (ERK-MAPK) (2 to 10 min), b) transcription activation of c-fos, c-jun and c-myc genes (10 to 30 min), c) induction of c-Fos and c-Myc proteins by 1 h and cyclin D1 protein by 5 h, and d) onset of DNA synthesis stimulation within 8 h. ACTH, itself a weak mitogen, interacts with FGF2 in a complex manner, blocking the FGF2 mitogenic response during the early and middle G1 phase, keeping ERK-MAPK activation and c-Fos and cyclin D1 induction at maximal levels, but post-transcriptionally inhibiting c-Myc expression. c-Fos and c-Jun proteins are mediators in both the strong and the weak mitogenic responses respectively triggered by FGF2 and ACTH. Induction of c-Fos and stimulation of DNA synthesis by ACTH are independent of PKA and are inhibited by the PKC inhibitor GF109203X. In addition, ACTH is a poor activator of ERK-MAPK, but c-Fos induction and DNA synthesis stimulation by ACTH are strongly inhibited by the inhibitor of MEK1 PD98059.
 ...
PMID:Proliferative signaling initiated in ACTH receptors. 1100 13

In vitro studies on the role of the mitogen-activated protein (MAP) kinase family (extracellular signal-regulated kinase [ERK], c-Jun NH(2)-terminal kinase [JNK], and p38) in cardiac hypertrophic response have produced confusing and contradictory results. We examined the in vivo role of the angiotensin II type 1 (AT(1)) receptor in cardiac MAP kinase activities during both the onset and development of cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP). In both the acute and chronic phases of cardiac hypertrophy in SHRSP, cardiac JNK activities were significantly increased compared with those in normotensive rats, whereas there was no prominent increase in cardiac ERK or p38 activities in SHRSP. Losartan, an AT(1) receptor antagonist, prevented the onset of cardiac hypertrophy and regressed the progression of cardiac hypertrophy in SHRSP, being accompanied by the reduction of JNK activity and activator protein-1 (AP-1) activity in SHRSP. However, in spite of the normalization of blood pressure, hydralazine did not prevent or regress cardiac hypertrophy and did not decrease JNK or AP-1 activity in SHRSP. Inversely, hydralazine significantly increased the cardiac ERK activity in SHRSP by enhancing its phosphorylation. In conclusion, we have obtained the first evidence that the AT(1) receptor is involved in the enhanced cardiac JNK activity in both the onset and development of cardiac hypertrophy of hypertensive rats. We propose that JNK is involved in AT(1) receptor-mediated cardiac hypertrophy in vivo, in part mediated by the activation of AP-1.
 ...
PMID:Important role of angiotensin II-mediated c-Jun NH(2)-terminal kinase activation in cardiac hypertrophy in hypertensive rats. 1104 Feb 28

Urinary trypsin inhibitor (UTI), a Kunitz-type protease inhibitor, interacts with cells as a negative modulator of the invasive cells. Human ovarian cancer cell line, HRA, was treated with phorbol ester (PMA) to evaluate the effect on expression of urokinase-type plasminogen activator (uPA), since the action of uPA has been implicated in matrix degradation and cell motility. Preincubation of the cells with UTI reduced the ability of PMA to trigger the uPA expression at the gene level and at the protein level. UTI-induced down-regulation of PMA-stimulated uPA expression is irreversible and is independent of a cytotoxic effect. Down-regulation of uPA by UTI is mediated by its binding to the cells. We next asked whether the mechanism of inhibition of uPA expression by UTI was due to interference with the protein kinase C second messenger system. An assay for PKC activity demonstrated that UTI does not directly inhibit the catalytic activity of PKC and that PMA translocation of PKC from cytosol to membrane was inhibited by UTI, indicating that UTI inhibits the activation cascade of PKC. PMA could also activate a signaling pathway involving MEK1/ERK2/c-Jun-dependent uPA expression. When cells were preincubated with UTI, we could detect suppression of phosphorylation of these proteins. Like several types of PKC inhibitor, UTI inhibited PMA-stimulated invasiveness. We conclude that UTI markedly suppresses the cell motility possibly through negative regulation of PKC- and MEK/ERK/c-Jun-dependent mechanisms, and that these changes in behavior are correlated with a coordinated down-regulation of uPA which is likely to contribute to the cell invasion processes.
 ...
PMID:Suppression of urokinase expression and invasiveness by urinary trypsin inhibitor is mediated through inhibition of protein kinase C- and MEK/ERK/c-Jun-dependent signaling pathways. 1105 91

Sulindac sulfone (Exisulind) induces apoptosis and exhibits cancer chemopreventive activity, but in contrast to sulindac, it does not inhibit cyclooxygenases 1 or 2. We found that sulindac sulfone and two potent derivatives, CP248 and CP461, inhibited the cyclic GMP (cGMP) phosphodiesterases (PDE) 2 and 5 in human colon cells, and these compounds caused rapid and sustained activation of the c-Jun NH2-terminal kinase 1 (JNK1). Rapid activation of stress-activated protein/ERK kinase 1 (SEK1) and mitogen-activated protein kinase kinase kinase (MEKK1), which are upstream of JNK1, was also observed. Other compounds that increase cellular levels of cGMP also activated JNK1, and an inhibitor of protein kinase G (PKG), Rp-8-pCPT-cGMPS, inhibited JNK1 activation by the sulindac sulfone derivatives. Expression of a dominant-negative JNK1 protein inhibited CP248-induced cleavage of poly(ADP-ribose) polymerase, a marker of apoptosis. Thus, it appears that sulindac sulfone and related compounds induce apoptosis, at least in part, through activation of PKG, which then activates the MEKK1-SEK1-JNK1 cascade. These studies also indicate a role for cGMP and PKG in the JNK pathway.
 ...
PMID:Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. 1105 Dec 67

In the present study, we investigated the effects of geranylgeraniol (GGO), a potent inducer of apoptosis in various lines of human tumor cells, on signal transduction cascades involved in apoptosis in human leukemia cells. GGO strongly induced the activation of c-Jun N-terminal kinase (JNK/SAPK) within 2 h in U937 and K562 cells, while neither ERK nor p38 was activated to any considerable extent during GGO-induced apoptosis. Transient expression of a constitutively active mutant form of mitogen-activated protein kinase kinase 1 (MEKK1), deltaMEKK1, or of deltaMEKK1-green fluorescent protein (GFP) in K562 cells activated JNK, but not a caspase-3-like protease, and was insufficient to induce cell death but rendered cells susceptible to GGO-induced cell death. Stable expressions of deltaMEKK1-GFP in U937 cells gave similar results. In contrast to VP-16-induced apoptosis, GGO-induced activation of JNK was almost completely inhibited by benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD) and by benzyloxycarbonyl-Asp-CH2OC[O]-2,6,-dichlorobenzene (Z-Asp), indicating that the JNK-activation step is located downstream of the caspase signaling pathway in GGO-induced apoptosis. Moreover, apoptosis induced by GGO was significantly inhibited in two lines of cells with a dominant-negative deletion mutation in c-Jun, indicating a requirement for JNK signaling. In addition, unlike the effects on other inducers of apoptosis, the activation of JNK and of the caspase-3-like protease by GGO was significantly delayed by 12-O-tetradecanoylphorbol-13-acetate (TPA), suggesting that the site of inhibition by TPA might be located upstream of the protease and JNK in the GGO-induced apoptotic signaling pathway.
 ...
PMID:The mechanism of geranylgeraniol-induced apoptosis involves activation, by a caspase-3-like protease, of a c-jun N-terminal kinase signaling cascade and differs from mechanisms of apoptosis induced by conventional chemotherapeutic drugs. 1108 77

In a previous study, we demonstrated that the length of glass fibers was a critical determinant of fiber potency in induction of tumor necrosis factor (TNF)-alpha and that activation of NF-kappaB was an important factor in this response. In the present study, we analyzed the role of mitogen-activated protein (MAP) kinases in the induction of TNF-alpha by glass fibers. Glass fibers induced phosphorylation of MAP kinases, p38, and ERK in primary rat alveolar macrophages, and this phosphorylation was associated with TNF-alpha gene expression. Long fibers were more potent than short fibers in activation of MAP kinases. Results from mechanistic analysis support that MAP kinases activate transcription factor c-Jun. The activated c-Jun acts on the TNF-alpha gene promoter through two binding sites, the cyclic AMP response element and the activator protein 1-binding site. These results suggest that in addition to the NF-kappaB pathway for TNF-alpha production, glass fibers are able to activate c-Jun through MAP kinase pathways that lead to induction of TNF-alpha expression.
 ...
PMID:Activation of mitogen-activated protein kinase p38 and extracellular signal-regulated kinase is involved in glass fiber-induced tumor necrosis factor-alpha production in macrophages. 1108 51

The aim of this study was to examine the role of mitogen-activated protein kinases (MAPKs) activation in bovine pulmonary arterial endothelial cells (EC) exposed to cyclic strain. EC were subjected to 10% average strain at 60 cycles/min. Cyclic strain induced activation of extracellular signal-regulated kinase (ERK; 1.5-fold), c-Jun NH(2)-terminal protein kinase (JNK; 1.9-fold), and p38 (1. 5-fold) with a peak at 30 min. To investigate the functional role of the activated MAPKs, we analyzed cells after treatment with PD-98059, a specific ERK kinase inhibitor, or SB-203580, a catalytic inhibitor for p38, and after transient transfection with JNK(K-R), and MEKK(K-M) the respective catalytically inactive mutants of JNK1 and MAPK kinase kinase-1. Cyclic strain increased activator protein-1 (AP-1) binding activity, which was blocked by PD-98059 and SB-203580. Activity of AP-1-dependent luciferase reporter driven by 12-O-tetradecanoyl-phorbol-13-acetate-responsive element (TRE) was induced by cyclic strain, and this was attenuated by PD-98059, MEKK(K-M), JNK(K-R), and SB-203580. PD-98059 and SB-203850 did not inhibit cell alignment and migration induced by cyclic strain. MEKK(K-M) and JNK(K-R) transfection did not block cyclic strain-induced cell alignment. In conclusion, cyclic strain activates ERK, JNK, and p38, and their activation plays a role in transcriptional activation of AP-1/TRE but not in cell alignment and migration changes in bovine pulmonary arterial EC.
 ...
PMID:Role of mitogen-activated protein kinases in pulmonary endothelial cells exposed to cyclic strain. 1109 May 94


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>